As part of an on going program examining the regulation of cyclic AMP accumulation in brain tissue, the current project is focussed on the study of mechanisms responsible for potentiative interaction between pairs of agonists. In the most extreme examples of this phenomenum, observed in slices of fetal guinea pig cerebral cortex, one member of the pair (e.g., alpha-adrenergic agonists, glutamate) produces no visible change in cyclic AMP accumulation in the absence of the other (e.g., histamine, adenosine). It is proposed to follow up observations suggesting that a major fraction of cyclic AMP accumulates in the extracellular space of slices by determining the impact of incubating slices in the presence of cyclic nucleotide phosphodiesterase or of potential inhibitors of cyclic AMP transport. In addition, primary cultures of fetal or neonatal cerebral cortical tissue will be used to examine the possibility that potentiative interaction involves augmentation of the transport of cyclic AMP into the medium by one member of a pair of agonists.